Visceral leishmaniasis, or Kala azar, is characterized by antigen-specific unresponsiveness in assays of cellular immunity, which reverses following cure. During a clinical trial of therapy with interferon gamma (IFN-gamma) monotherapy, we measured mRNA levels of several cytokines in serial splenic aspirates to follow the immune response. Five of nine patients had a partial clinical response, yet all eventually required standard antimony therapy. The high levels of pretreatment IFN-gamma mRNA decreased in all patients during the course of monotherapy, but returned to baseline by the end of treatment. IL-10 message was high before and during treatment in all patients receiving monotherapy, and only declined to low levels in patients following standard therapy cure. The high levels of this counter regulatory cytokine might be responsible for the inhibition of either endogenous or exogenous IFN-gamma-mediated control mechanisms. The therapeutic potential of anti-IL-10 antibodies administered alone or in combination with antimony of IFN-gamma will be investigated in mouse models of visceral disease. Two additional aspects of Indian Kala azar are currently being studied. Over 50% of the Kala azar cases from the Indian state of Bihar are unresponsive to standard antimony therapy. There is as yet no formal evidence that treatment failure is due to the appearance of drug resistant parasites. Isolates from responsive and refractory cases have been obtained and are currently being tested in vitro and in vivo assays for antimony sensitivity. The finding that some cases of visceral leishmaniasis in North India are due not to L. donovani, but to L. tropica species, is being pursued by comparing the visceral isolates with more typical cutaneous L. tropica strains for virulence and tissue tropism in animal models. The identification and purification of metacyclic promastigotes of L. tropica strains permitted the first successful animal models for L. tropica infections to be developed. Only cutaneous strains were able to produce clinically apparent cutaneous lesions in BALB/c mice. The role of sand fly saliva in promoting the development of visceral disease will be investigated. In the past year, seven patients with known or suspected leishmaniasis were referred to the NIH. Three patients were tourists, three were Peace Corps volunteers, and one was a Smithsonian Museum employee. One patient with L. mexicana failed to cure with one course of antimony, and was given a second course plus INF-gamma.